The coronavirus 2019 (COVID-19) pandemic has interrupted social and economic activity and has led to a huge wave of sickness and death. However, there are other healthcare costs as well, one of which is the interruption of scheduled screening for diseases that can be cured if diagnosed early; one such disease is cervical cancer.
A new study reveals inequalities in the delay in screening for this cancer, and recommends that the screening capacity be increased in addition to giving a higher priority to women who have missed their scheduled visit.
Cervical screenings aim to identify early signs of cervical malignancy to enable timely extirpation of malignant cells before they invade the underlying tissue and spread to form overt cancer.
The current study, published as a preprint on the medRxiv* server in November 2020, was based in the UK, where cervical screening is conducted by nurses trained to take samples as part of general practice.
Cervical screening and cancer odds in England
The incidence of cervical cancer in England, standardized by European age-linked risk, is about 9.5/1,00,000 between 25 and 64 years. The screening schedule envisages a 3-yearly screening between 25 and 49 years (which may now extend to 5 years with primary HPV testing being now available), and a 5-yearly screening between 50 and 64 years. About 72% of eligible women participate at present.
The researchers estimated the odds for this cancer in women who were a) called the first time for screening, b) recalled for future routine screenings, and c) those outside the program. According to the primary HPV screening round, conducted on mostly unvaccinated women, around 7%, 2% and 0.5% of women in the age groups 25 to 29 years, 30 to 49 years, and 50 to 64 years, respectively, had high-grade cervical intraepithelial neoplasia (CIN) grade 2 or higher, at the first call, the first recall or second recall.
Vaccination against the human papillomavirus (HPV) is offered to girls above 12 years in England, and about 86% of 12-13-year old girls take the vaccine. This is expected to steeply reduce the incidence of cervical cancer. The odds of the high-grade premalignant condition called cervical intraepithelial neoplasia (CIN) grade 3 or higher were reduced by 86% among those vaccinated by 13 years; 78% in those vaccinated by 14; 73% by 16 years; 45% by 17 years; and only 15% if vaccinated by 18 years.
The researchers also estimated the proportion of CIN that would develop into cervical cancer within 6 months. They found that for those below 30 years, the progression rate to asymptomatic cancer was just above 1 in 1,000 at 24-29 years, doubling at 30-34 years, and tripling to 0.35% at 35-39 years. By 40-49 years, it was six-fold, at 0.65%.
Beyond this, the rate of progression increased by almost an order of magnitude, to 9 in 1,000 by 50-61 years, and 11 in 1,000 for women aged 62 years or more.
Cervical screening during COVID-19
Screening for cervical cancer was hit hard by the pandemic, not only in the UK but everywhere. In the UK, women were not invited for their screening visit from April 2020 onwards to June 2020. Even at this second time point, physicians could push the invitations for screening by 6 months more, if required. Similar delays could accompany future resurgences of the virus.
Already, there is a significant backlog of women waiting for their screening, ever since GPs began to offer only urgent consultations in March 2020. Nobody can predict how fast this can be caught up to pre-pandemic levels, at both practice and laboratory levels, nor is it clear how many women will come in for screening even if routine screening is resumed. However, scientists can estimate the amount of excessive cancer risk that is likely to ensue because of the missed screening opportunity.
Catching up on screening services: two scenarios
The health service can now do one of two things: it can reschedule the whole program, ‘dropping’ the six months of non-screening to start afresh, or it can reschedule screening for only those women who missed their turns. Those who would have been invited later on, in any case, continue their schedules without a break.
In the first case, screening would be permanently moved down by six months for all women already in the program, but not for those who newly enter the program after the current disruption has been resolved. The population affected in the first case will be 3-fold or 5-fold the total number of women in a year.
In the second case, only some women will suffer – those whose invitations fell within the delay period – as they are not offered the opportunity to catch up. Their next screening will happen only after 3 or 5 years, depending on their age group. This will affect half the total number of women screened in a year.
Impact of these scenarios
The current study uses mathematical modeling to understand the impact of both these approaches on women between 25 and 64 years of age in terms of cervical cancer incidence in England. This was used to estimate the total number of women with such conditions who were not diagnosed because of delayed screening, after adjusting for the protective effect of three rounds of vaccination on women aged 25 to 34 years.
Abolishing screening for the whole group would lead to a loss of screening for about 10.7 million women, versus 1.5 million women if only the women whose turns came during the pandemic period were affected. Though these numbers appear vastly different, the number of women who developed cancer in excess of that which would be expected with regular screening hovered around 630 in both scenarios. This comes to about 4 cases in addition to the typical count per screening cycle per 1,00,000 women.
Missed screening cycles associated with 7-Fold cancer risk
When stratified by age, the excess cancer diagnoses are found to be highest in the 40-49-year age group, and least in the 25-34-year age group who have received vaccination against high-risk HPV strains.
The effect of the interruption in screening thus results, not in an absolute increase in the number of cancers, but in the distribution of these cases. The women who are forced to forego screening due to COVID-19-related restrictions bear the brunt of the additional risk, due to their CIN having far longer time to progress before its detection. This also means their cancers are likely to be more advanced at the time of detection.
In the second scenario, therefore, the risk of cancer would be seven times higher in a woman who missed the screening than if she was screened with a delay of 6 months. The rates of excess cancer would be 41.5 and 5.9 per 1,00,000 women, respectively.
The validation of these findings is complicated by the long latent period of cervical cancer, the expected rise in diagnoses with the initiation of HPV screening at the primary care level due to its increased sensitivity for this condition, relative to cytologic assessment. The researchers comment, “Evaluation of screening histories from women diagnosed with cervical cancer once screening services resume will provide the best evidence of the actual impact of 151 COVID-19 delays to cervical screening.”
What are the implications?
The researchers point out, “In the name of equity, therefore, our analysis calls for measures that ensure that women do not miss an entire screening round on account of the COVID-19 disruption, i.e. scenario 2 should be avoided and scenario 1 would be preferable.”
Though this would mean an increase in risk to a much larger number of women, it may be possible to boost screening capacity for a few months to catch up with the backlog and thus reduce the excessive risk over a shorter period. The obvious flaw in this strategy, as the investigators highlight, is the fact that HPV testing and COVID-19 testing use the same set of reagents, directly affecting reagent availability.
Nonetheless, this should be pursued as far as possible, and women whose appointments are overdue should be encouraged as far as possible to come in for early screening, to minimize the harm. This demands that they be first identified, a difficult enough task at the primary care level, but one which should be prioritized to ensure equitable distribution of care to this group.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.